This application is part of a consortium application between the University of North Carolina and Duke University. Ionizing radiation induces acute intestinal injury that targets the rapidly dividing intestinal epithelial cells and is perpetuated by an inflammatory process that is mediated by innate immune cells. Commensal bacteria, dominated by colonic anaerobes, contain a large number of components that can activate innate immune responses by ligating membrane-bound and intracellular receptors that activate signaling cascades that include NFkB and MAP kinases. Membrane pattern recognition receptors include toll-like receptors (TLR), while intracellular receptors include members of the CATERPILLER family, with the intestinal prototype being NOD 2/CARD 15, which has been implicated in a subset of Crohn's disease patients. Studies in animal models of intestinal inflammation demonstrate that ligation of these receptors can have both beneficial and detrimental effects, with a suggestion that activation of NFkB of epithelial cells is protective but that NFkB activation in lamina propria innate immune cells induces inflammation. Our studies in gnotobiotic mice and rats demonstrate a primary role for commensal bacterial adjuvants and antigens in the induction of acute and chronic experimental intestinal inflammation. Endogenous interleukin 10 (IL-10) is an important protective factor that downregulates innate and acquired immune responses to commensal bacteria. This regulatory cytokine is produced by innate immune cells and T lymphocytes in response to activation by commensal bacterial products. We will study the hypothesis that commensal bacterial products activate innate immune responses that potentiate intestinal inflammation induced by exposure to radiation. We will develop therapeutic strategies to prevent inflammation and promote mucosal healing.